Disturbed retinoid metabolism upon loss of rlbp1a impairs cone function and leads to subretinal lipid deposits and photoreceptor degeneration in the zebrafish retina.
Disturbed retinoid metabolism upon loss of rlbp1a impairs cone function and leads to subretinal lipid deposits and photoreceptor degeneration in the zebrafish retina.
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DOI：
10.7554/elife.71473
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发表时间：
2021-10-20
期刊：
影响因子：
7.7
通讯作者：
Neuhauss SC
中科院分区：
文献类型：
--
作者：
Schlegel DK;Ramkumar S;von Lintig J;Neuhauss SC
RLBP 1基因编码36 kDa的细胞视黄酸脱结合蛋白，CRALBP，一种可溶性视黄酸载体，在眼睛的视觉周期。RLBP 1的突变与隐性遗传的临床表型相关，包括波的尼亚营养不良、色素性视网膜炎、白斑性视网膜炎、白斑性眼底病和纽芬兰视杆-视锥营养不良。然而，这些视网膜疾病的病因还没有很好地理解。在这里，我们生成了同源斑马鱼模型来弥合这一知识差距。斑马鱼中rlbp 1基因的复制以及视网膜色素上皮中旁系同源物rlbp 1a和Müller神经胶质细胞中rlbp 1b的细胞特异性表达使我们能够创建固有的细胞类型特异性敲除鱼系。利用rlbp 1a和rlbp 1b单突变体和双突变体，我们研究了视功能的病理影响。我们的分析表明，rlbp 1a是必不可少的锥光感受器的功能和发色团的代谢在鱼的眼睛。RLBP 1A突变的鱼表现出降低的发色团水平和减弱的视锥光感受器对光刺激的反应。他们积累了11-顺式和全反式视黄酯，这些酯在RPE中显示为增大的脂滴，使人联想到RLBP 1突变患者的视网膜下黄白色病变。在衰老过程中，这些鱼发展成视网膜变薄和视锥和视杆细胞营养不良。相比之下，rlbp 1b突变体没有显示视力受损。双突变体基本上复制了rlbp 1a单突变体的表型。总之，我们的研究表明，rlbp 1a斑马鱼突变体重现了RLBP 1突变引起的人类致盲疾病的许多特征，并为锥状光感受器的发色团再生途径提供了新的见解。
The RLBP1 gene encodes the 36 kDa cellular retinaldehyde-binding protein, CRALBP, a soluble retinoid carrier, in the visual cycle of the eyes. Mutations in RLBP1 are associated with recessively inherited clinical phenotypes, including Bothnia dystrophy, retinitis pigmentosa, retinitis punctata albescens, fundus albipunctatus, and Newfoundland rod–cone dystrophy. However, the etiology of these retinal disorders is not well understood. Here, we generated homologous zebrafish models to bridge this knowledge gap. Duplication of the rlbp1 gene in zebrafish and cell-specific expression of the paralogs rlbp1a in the retinal pigment epithelium and rlbp1b in Müller glial cells allowed us to create intrinsically cell type-specific knockout fish lines. Using rlbp1a and rlbp1b single and double mutants, we investigated the pathological effects on visual function. Our analyses revealed that rlbp1a was essential for cone photoreceptor function and chromophore metabolism in the fish eyes. rlbp1a-mutant fish displayed reduced chromophore levels and attenuated cone photoreceptor responses to light stimuli. They accumulated 11-cis and all-trans-retinyl esters which displayed as enlarged lipid droplets in the RPE reminiscent of the subretinal yellow-white lesions in patients with RLBP1 mutations. During aging, these fish developed retinal thinning and cone and rod photoreceptor dystrophy. In contrast, rlbp1b mutants did not display impaired vision. The double mutant essentially replicated the phenotype of the rlbp1a single mutant. Together, our study showed that the rlbp1a zebrafish mutant recapitulated many features of human blinding diseases caused by RLBP1 mutations and provided novel insights into the pathways for chromophore regeneration of cone photoreceptors.